Obsessive-compulsive disorder has been studied from several different perspectives since this project began in 1980. During the past year, we have focused primarily on the treatment of this disorder. Previously we showed that the tricyclic antidepressant clomipramine was specifically anti-obsessional, in contrast to several other antidepressants. As clomipramine is considerably more potent than other tricyclic antidepressants in its serotonergic effects, we hypothesized that these effects might be important for its anti-obsessional properties. To test this hypothesis, we extended our earlier findings that the selective serotonin postsynaptic receptor agonist m-chlorophenylpiperazine (m-CPP) increased obsessional symptoms by retesting obsessive- compulsive disorder patients after chronic treatment with clomipramine. Following treatment, patients showed less of a response to m-CPP, suggesting that clomipramine was associated with postsynaptic subsensitivity. Furthermore, metergoline, a serotonin receptor antagonist, appeared to partly reverse the effects of chronic clomipramine treatment. These results, taken together with recent findings from other investigators correlating clinical improvement on clomipramine with changes in serotonin function, strongly suggest that the drug's serotonergic effects are integral to its clinical efficacy for obsessive-compulsive disorder. Although we have learned much about the biochemical mechanism of clomipramine's action, results from another study reminded us of the limitations of this treatment. Of 18 patients discontinued from chronic clomipramine treatment, 17 relapsed within 7 weeks. Clearly, the drug is a treatment not a cure. Our continued follow-up studies of these patients have revealed the importance of nonpharmacologic factors in outcome.